Hylke Salverda

114 Chapter 6 The lack of effect of AOC on clinical outcome could be attributed to several causes. Some of the outcomes being assessed are relatively uncommon, and although we compared two large cohorts, effect sizes in outcome differences are likely to be small given the power in the study. Secondly, in our earlier study16 the increased time in TR while using AOC was mainly attributable to a substantial decrease in SpO2 values above TR, whereas the time with SpO2 <80% was similar to manual titration. It could be that outcome is more largely influenced by the frequency and duration of hypoxia and hypoxic events,36 and by time above TR to a lesser extent. Finally, several changes to standard of care have been made during the study span which could have simultaneously influenced the outcome in either direction. For example, in November 2014 the lower limit of the TR was changed from 85% to 90% (likely narrowing the SpO2 distribution and shifting it to the right), and minimally invasive surfactant therapy was introduced. There may have been other factors we did not measure. A limitation of this study could be these unmeasured factors as they are not adjusted for. It is conceivable and plausible that the introduction of AOC has contributed to a shift toward more non-invasive ventilation in our NICU. It may have contributed in two ways, firstly by rendering more stability to oxygenation and secondly by reducing the baseline oxygen requirement, as a direct consequence of continuous titration of FiO2 to target the midpoint of the SpO2 range. Although the retrospective nature of this study precludes the drawing of a definitive conclusion, the shift towards more non-invasive ventilation could prove promising. Prolonged mechanical ventilation is a risk factor for complications and has been directly associated with poor neurodevelopmental outcome. 37. In planned further studies, follow-up outcomes at 2 years will be compared between these cohorts. Beyond its retrospective nature, another limitation of our study is that the actual time infants received AOC was not recorded. Local policy is to disable AOC once SpO2 values >98% are recorded continuously for 30 minutes without supplemental oxygen, and thus it is possible that some infants only received AOC during a short period, diminishing any treatment effect. However, as we took the entire sample of patients admitted during the period of 2012-2018, the results are likely to be generalisable for NICUs in similar settings.